Polyalkylenebisaniline anesthetics



2,993,831 I I POLYALKYLENEBISANILINE ANESTHETHIS Seymour 1.. Shapiro,Hastings on Hudson, and Louis Freedman, Bronxville, N.Y., assignors toUS. Vitamin & Pharmaceutical Corporation, New York, N.Y., a corporationof Delaware No Drawing. Filed June 18, 1958, Ser. No. 742,752 3 Claims.(Cl. 167- 52) This invention is concerned with certainN,N'-polymethylene bis(2,6-dimethylanilines) which are unusuallyeffective anesthetic agents and with the process for their preparation.

Specifically, we have now found that compounds of the structure 'wherein11:3-5, are potent anesthetic agents with desirable lack of toxicity.

If n is larger than 5 the anesthetic effect is considerably diminished,whereas replacement of the methyl groups by ethyl groups in the 2,6positions of the aniline rings is also accompanied by diminishedanesthetic 'eifect. A further requisite for the structures within thissystem is that the nitrogen atoms have hydrogen groups attached. Ifthese hydrogen atoms are replaced by methyl groups, anesthetic effect isreduced. Of particular significance is the stability of these activeagents, with none of the groupings being vulnerable to hydrolysis.

The criticality in the structural requirements for pronounced anestheticactivity is manifest from Table I.

The compounds were evaluated by the method of Chance and Lobstein, J.Pharmacol, 82, 203 (1944), for determining the median effective dose ofa local anesthetic when applied to the cornea of a guinea pig eye.

A known concentration of solution of the local anesthetic is applied toboth eyes of a guinea pig and the eyes kept bathed with this solutionfor two minutes. The eyes are then blotted to remove excess solution.

Five minutes later, the eyes are tested for the anesthetic effect. Ahorse hair mounted on a glass rod is used. The hair is pressed againstthe center of the cornea so that the hair is bent to about the sameextent at each application. The hair is applied times to each eye, andthe process repeated 5 times for the test (total of 100 prods). Theresult is reported thus: 100 minus number of blinks=percent anesthesia.

' rates Patent halide, suitably Br(CH ),,Br.

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Varying concentrations of the anesthetic agent are used and the percentanesthesia is plotted against concentration. The results are expressedas the ED in mg./ml. which is the quantity of compound per milliliter ofsolution required to effect 50% anesthesia as established from the plotof concentration vs. percent anesthesia.

The toxicity of the individual compounds was established byadministration subcutaneously (s.c.) to mice, in terms of the minimumdose required to be lethal to mice and expressed as LD in milligrams ofcompound per kilogram of mouse.

The therapeutic index was then calculated by dividing the LD by the EDthe result being a single figure embracing the anesthetic effectivenessof the compound and its inherent toxicity.

The selected compounds of this invention are bases and are desirablysolubilized when used as their salts with strong acids such ashydrochloric, hydrobromic, sulfuric and the like.

The compounds of the type shown in Formula I where n=3 and 5 areconveniently prepared by the reaction of an excess of2,6-dimethylaniline with the appropriate The compound where n-=5 hasbeen reported by Sommers et al., J. Am. Chem. Soc., 75, 5280 (1953),with no indication of its utility as an anesthetic agent. However, theattempted preparation of the compound where 11:4 could not be realizedby this reaction since even in the presence of an excess of the2,6-dimethylaniline, the reaction favored was apparently that where thecompound cyclized as shown in the equation below.

CH5 CH .l H Br l H Br CH3 CH3 shown in the scheme I below.

The process and compounds of this invention will be more clearlyunderstood from a consideration of the following specific examples whichare given for the pur pose of illustration only and are not to beconstrued as limiting the scope of the invention in any way.

EXAMPLE 1 A mixture of 66.5 g. (0.55 mole) of 2,6-dimethylani1ine and22.2 g. (0.11 mole) of trimethylene dibromide was heated on the steambath for 3 hours. When cool, the formed crystals were separated, rinsedwith ether, dried and dissolved in 150 ml. of water. The aqueoussolution was rendered alkaline by the addition of 6 N sodium hydroxideand the liberated base extracted with three 200-ml. portions of ether.The combined ether extracts were dried (anhydrous magnesium sulfate),filtered, the ether removed and the residue distilled. There wasobtained 13.0 g. (50%) of N,N-trimethylene-bis(2,6-dimethylaniline),B.P. 172174 C. (0.2 mm.).

The product crystallized on standing, M.P. 7173 C.

Analysis.-Calcd. for C H N C, 80.8; H, 9.3; N, 9.9. Found: C, 81.1; H,8.9; N, 10.0.

EXAMPLE 2 A solution of 9.3 g. (0.06 mole) of succinyl chloride in 60ml. of ether was added gradually with stirring to a solution of 29.0 g.(0.24 mole) of 2,6-dimethylaniline in 200 ml. of ether. After theaddition, stirring was continued for 40 minutes and the mixture ofproduct and 2,6- dimethylaniline hydrochloride separated, washed withether and then with water. The water-insoluble product N,Nbis(2,6-dimethylphenyl)succinamide, 24.9 g. (90%), melted at 322-323 C.after recrystallization from methyl Cellosolve.

Analysis.Calcd. for C H N O C, 74.0; H, 7.5; N, 8.6. Found: C, 73.8; H,6.9; N, 8.7.

There was similarly prepared from 2,6-dimethylaniline and malonylchloride, N,N'-bis(2,6-dimethylpheuyl) malonarnide, M.P. 266267 C.

Analysis.-Calcd. for C H N O C, 73.5; H, 7.1; N, 9.0. Found: c, 73.1; H,7.3; N, 8.9.

There was similarly prepared from 2,6-dimethylaniline and adipylchloride, N,N-bis(2,6-dirnethylphenyl)adipamide, M.P. 290-292 C.

Analysis.-Calcd. for C H N O C, H, N,

7.9. Found: C, 75.1; H, 8.2; N, 8.2.

EXAMPLE 3 the residue separated and rinsed with two 300-m1. portions ofether. The combined filtrates were concentrated to about 25 ml. and onstanding at C., 5.9 g. (47.5%) of the product separated, M.P. 145-148C., recrystallized (heptane) M.P. 149-150" C.

V 4,. q I 4 Analysis.-Calcd. for C H N O: C, 77.4; H, 8.4.

Found: C, 77.5; H, 8.0.

EXAMPLE 4:

N,N'-tetramethylene-bis(2,6-dimethylaniline) was obtained as follows: Amixture of 1.52 g. (0.04 mole) of lithium aluminum hydride in 300 ml. ofether was treated With a slurry of 4.65 g. (0.015 mole) of('y-[2,6-dimethylanilino]-butyr)-2,6-dimethylanilide in 300 ml. ofether. After stirring under reflux for 30 hours and standing for anadditional hours, 1.0 ml. of water followed by 1.0 ml. of saturatedsodium chloride and 2.25 ml. of 40% sodium hydroxide solution was added.The formed granular precipitate was separated, rinsed with ether and thecombined ether filtrates concentrated. Unreacted anjlide (2.4 g.)precipitated and was separated. The filtrate was evaporated to yield aresidue which was distilled. There was obtained 1.11 g. (25%) of productboiling at 172182 C. (0.11 mm.). On standing at room temperature theproduct crystallized, M.P. 61-63 C., recrystallized (pentane) M.P. 7273C.

Analysis.Calcd. for C H N C, 81.0; H, 9.5; N, 9.5. Found: C, 81.1; H,9.4; N, 9.7.

It is to be understood that it is intended to cover all changes andmodifications of the examples of the invention herein chosen for thepurpose of illustration which do not constitute departure from thespirit and scope of the invention.

We claim:

1. A process for inducing anesthesia in a veterinary animal whichcomprises administering parenterally an effective amount of a compoundof the formula CH3 CH3 CH5 CH8 where n is an integer selected from thegroup consisting of 3 and 5, said compound being in unit dosage form.

2. The process of claim 1 where n=3. 3. The process of claim 1 wheren=5.

References Cited in the file of this patent OTHER REFERENCES Beilstein,vol. 12, 1929, pp. 828, 1110. Chem. Abst., vol. 49, 1955, p. 317 (at cand e).

1. A PROCESS FOR INDUCING ANESTHESIA IN A VETERINARY ANIMAL WHICHCOMPRISES ADMINISTERING PARATERALLY AN EFFECTIVE AMOUNT OF A COMPOUND OFTHE FORMULA WHERE N IS AN INTEGER SELECTED FROM THE GROUP CONSISTING OF3 AND 5, SAID COMPOUND BEING IN UNIT DOSAGE FORM.